tbuckley/cabot-search huggingface dataset:
Abstract 126: Extreme selection constrains ability of EGFR-driven lung adenocarcinoma to diversify in response to erlotinib therapy
Authors: J Nicholas Fisk, Stephen Gaffney, Katerina Politi, Scott Gettinger, Fernando de Miguel, Jeffrey Townsend
Journal: Cancer Research (2023)

Abstract The acquisition of resistance by tumors to targeted molecular therapies remains one of the greatest challenges in precision medicine. Evolutionary techniques, such as phylogenetic analysis and the thoughtful calculation of selection intensities, are well suited to offer guiding insights in describing and, ultimately, overcoming therapeutic resistance. Here, we quantify the relative importance of mutations occurring during EGFR targeted therapy on a cohort of Lung Adenocarcinoma (LUAD) patients using clinical records to calibrate phylogenetic chronograms to identify variants occurring on branches of the tumor phylogeny coinciding with targeted EGFR therapy and calculate the evolutionarily-derived cancer effect size for those variants. We then compare these results to other cancer contexts to reveal the strikingly high effect size of the EGFR T790M mutation. To probe and quantify the constraints therapeutically driven selection pressure places on the cohort, we predict the neoantigen composition for each patient for both extant and ancestral tumor states, using a general allele frequency selection model to calculate selection on cancer variants constituting putative neoantigens. We then compare the proportion of negatively and positively selected neoantigens to non-neoantigen variants within the tumor to deduce if neoantigens are subject to additional immune scrutiny in a background of therapeutics. Lastly, we perform ancestral state reconstruction and mutational signature analysis to provide further insight on mutational processes on both individual patient and cohort levels, detailing how these endogenous and exogenous processes shift between etiologically pertinent time-points. Taken together, our results detail the degree of selection on cancer undergoing targeted therapy and highlights unique shifts in mutational processes in response to such therapies, ultimately offering quantitative insights that can inform clinical decision making regarding therapeutic strategies in Lung Adenocarcinoma and provide a framework for analyzing similar cancer systems. Citation Format: J Nicholas Fisk, Stephen Gaffney, Katerina Politi, Scott Gettinger, Fernando de Miguel, Jeffrey Townsend. Extreme selection constrains ability of EGFR-driven lung adenocarcinoma to diversify in response to erlotinib therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 126.
Abstract 6271: Discovery of BR1733 for the treatment of SWI/SNF deficient or highly vascularized solid tumor
Authors: Xinghao Wang, Shichao Ma, Min (Bella) Xie, Lele Wang, Yajun Wang, Song Zhang, Sheng Chen, Lynette Zhang, Yongqi Zhou, Mengxi Zhao, Dandan Li, Guobin Li, Xiao Fan, Hailong Zhang
Journal: Cancer Research (2023)

Abstract Polycomb repressive complex 2 (PRC2) catalyze the writing of H3K27me3 epigenetic marker and suppresses the expression of genes including tumor suppressors. Activation mutation of EZH2, the catalytic subunit of the PRC2 complex, drives the progression of tumors such as DLBCL. The embryonic ectoderm development (EED) protein acts as the scaffolding and H3K27me3-binding subunit of PRC2 and is essential for its activity. We have developed potent, selective, and orally bioavailable EED inhibitor BR1733. BR1733 blocks the interaction between EED and H3K27me3, and inhibits catalytic activity of PRC2. BR1733 showed superior PK profile across species and exhibited tumor growth inhibition against several B cell lymphoma CDX models. Indication expansion studies demonstrated that BR1733 could inhibit solid tumors with SWI/SNF loss-of-function mutation only when both CDKN2A and TET1 are expressed. BR1733 also inhibited tumor angiogenesis and showed tumor growth inhibition in several CDX models of highly vascularized solid tumors such as HCC and RCC. BR1733 is currently in Phase I clinical trials. Citation Format: Xinghao Wang, Shichao Ma, Min (Bella) Xie, Lele Wang, Yajun Wang, Song Zhang, Sheng Chen, Lynette Zhang, Yongqi Zhou, Mengxi Zhao, Dandan Li, Guobin Li, Xiao Fan, Hailong Zhang. Discovery of BR1733 for the treatment of SWI/SNF deficient or highly vascularized solid tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6271.
Abstract 5219: Telomere length distribution, metabolic trait association, and genome-wide association study among Singaporean cohorts
Authors: Trang Nguyen, Penny Chan, Ives Lim, Brian Kennedy, Neerja Karnani, Rajkumar Dorajoo, Joanne Ngeow
Journal: Cancer Research (2023)

Abstract Leukocyte telomere length (LTL) is known as a heritable marker of cellular aging and is a risk factor for several chronic diseases. LTL distribution and association studies are essential in providing insights into telomere homeostasis, its relationship with different metabolic traits, and age-related conditions. Such studies have been underperformed in Asian population groups. Here we estimated LTL using whole-genome sequencing data in 8,045 Singaporean samples across three major ethnic groups - Chinese, Indian, and Malay divided into six cohorts: GUSTO, HELIOS, MEC, PRISM, SEED, and TTSH. LTLs were measured using TelSeq, with normalized LTL as phenotype in subsequent analyses. We demonstrated that average LTL was robustly longer in the childhood cohort (GUSTO) compared to the adult cohorts (P&amp;lt;1.19 × 10−195). We observed ethnicity differences in LTL where adult Singaporean Chinese samples had the longest LTL (5.08kb) as compared to Malay (4.87kb) and Indian (4.65kb) samples in our datasets (P&amp;lt;4.98 × 10−12). Our genetic association analyses replicated multiple variants previously reported to be associated with LTL (binomial P&amp;lt;0.00001) in Asian population groups, providing added confidence in the methodologies used. At the same time, we identified a novel East-Asian-specific novel variant beyond genome-wide association levels (meta P=2.05 × 10−08) at the COL28A1/MIOS gene loci to be associated with LTL in our study. Individual analysis of the GUSTO childhood dataset highlighted a second novel genome-wide hit at RAD17 gene locus to be associated with LTL in our study and indicated that the previously reported variant at the TINF2 locus may have significantly opposing effects (compared to adults) during early developmental stages. Gene-level burden analysis for rare variants (MAF &amp;lt;5%) in adult Chinese cohorts revealed potential cancer association with RET gene (SKAT, P=5.22 × 10−03) and MLH1 gene (SKAT, P=0.037), as well as telomere biology condition association with RECQL4 gene (CMC, P=0.0399, and VT, P=0.0379). Our findings have broadened the understanding of LTL distribution and the underlying associated genetic characteristics in both childhood and adult Singaporean populations. Citation Format: Trang Nguyen, Penny Chan, Ives Lim, Brian Kennedy, Neerja Karnani, Rajkumar Dorajoo, Joanne Ngeow. Telomere length distribution, metabolic trait association, and genome-wide association study among Singaporean cohorts. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5219.
Abstract 1574: Homoharringtonine is effective in treating acute lymphoblastic leukaemia via modulation of apoptotic pathway
Authors: Anan Jiao, Kei Ching Yuen, Rahman Ud DIN, On Yi Phoebe Wong, Sin Chun-Fung
Journal: Cancer Research (2023)

Abstract Acute lymphoblastic leukaemia (ALL) is an aggressive and highly lethal malignancy caused by clonal mutations in lymphoid progenitor cells. The prognosis for adult ALL remains poor, with only 30-40% of adult patients achieving long-term remission. Therefore, novel therapies are needed. Homoharringtonine (HHT) is a natural-derived plant alkaloid from tree of Cephalotaxus. FDA approved the use of HHT in the treatment of chronic myeloid leukaemia (CML) in 2012. Limited pre-clinical or clinical studies were conducted for therapeutic efficacy and molecular mechanisms of HHT on ALL to the best of our knowledge. To fill this knowledge gap, here we investigated the antileukemic activity of HHT in T lymphoblastic leukaemia (T-ALL) and B lymphoblastic leukaemia (B-ALL). In this study, T-ALL cell lines namely JURKAT, MOLT-4, LOUCY, CCRF-CEM and B-ALL cell clines namely PALL-2, SUP-B15 were used. Cell viability was reduced upon treatment of HHT at time and dose-dependent manner. Percentage of apoptotic cells that determined by flow cytometric analysis of PI and Annexin V double staining was increased upon treatment of HHT. Moreover, HHT was able to induce apoptosis in both T-ALL and B-ALL cell lines. Western blot analysis showed that MCL-1 protein level was reduced upon treating with HHT for 24 hours. The above findings provide conclusive evidence for the therapeutic effect of HHT on various ALL cell lines by modulating the apoptotic pathway. Citation Format: Anan Jiao, Kei Ching Yuen, Rahman Ud DIN, On Yi Phoebe Wong, Sin Chun-Fung. Homoharringtonine is effective in treating acute lymphoblastic leukaemia via modulation of apoptotic pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1574.
Abstract 4448: Chemokine (C-X-C motif) ligand 17 promotes cutaneous squamous cell carcinoma via modulating tumor-immune evasion
Authors: Alok R. Khandelwal, Rema Anisha Kandula, Emily Daniel, Md Maksudul Alam, Henry Craighead, Tara Moore-Medlin, Cherie-Ann O. Nathan
Journal: Cancer Research (2023)

Abstract Cutaneous squamous cell carcinoma (cSCC) is a keratinocyte-derived invasive and metastatic tumor of the skin. It is the second-most commonly diagnosed form of skin cancer, striking 200,000 Americans annually. Further, organ transplant patients are at significantly increased risk of cSCC compared to the general population. Excision of cSCC of the head and neck area results in significant facial disfigurement. An increased understanding of the mechanisms involved in the pathogenesis of cSCC could identify means to prevent, inhibit, and reverse this process. Chemokine (C-X-C motif) ligand 17 (CXCL17) is the latest chemokine family member, and an increased CXCL17 protein expression was observed in both mouse and human cSCC cell lines. Further, deletion of CXCL17 was associated with significant inhibition of tumor cell-intrinsic properties such as proliferation, migration, and motility. CXCL17 is identified as a potent chemoattractant for macrophages, dendritic cells and myeloid-derived suppressive cells. Accordingly, utilizing a syngeneic, tumor-cell xenograft cSCC mouse model, we evaluated the effect of CXCL17 deletion on cSCC tumor-immune evasion and elucidated the underlying mechanism. Deletion of CXCL17 was associated with a significant reduction in tumor volume compared to the wild-type counterparts. Further, CXCL17 deleted cSCC tumor cell xenografts exhibited a significant increase in CD8+, cytotoxic T cells in the tumor microenvironment, suggesting an important role of CXCL17 in mediating tumor-immune evasion. Interestingly, treatment with CXCL17 induced macrophage M2 polarization and promoted macrophage efferocytosis via modulating efferocytotic machinery proteins such as MERTK, TIM4, GAS6 and AXL. Our studies have established substantial evidence for the role of CXCL17 in modulating tumor-cell extrinsic properties to affect the progression of cSCC. Citation Format: Alok R. Khandelwal, Rema Anisha Kandula, Emily Daniel, Md Maksudul Alam, Henry Craighead, Tara Moore-Medlin, Cherie-Ann O. Nathan. Chemokine (C-X-C motif) ligand 17 promotes cutaneous squamous cell carcinoma via modulating tumor-immune evasion. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4448.
Abstract 1582: Inhibition of autophagy by CAGE targeting peptide retard tumor growth in non-small cell lung cancer of EGFR TKI resistance
Authors: Jung-Young Shin, Min-Young Kim, Mi-Ran Lee, Hankyu Lee, Doyong Jeon, Seung Ryel Baek, Kim Joo Il, Jaemoon Koh, Dooil Jeoung, Jin Hyoung Kang
Journal: Cancer Research (2023)

Abstract Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) is the standard of care as 1st-line treatment for NSCLC patients with activating EGFR mutations (exon 19 deletion or L858R mutation). However, EGFR-TKI therapy eventually leads to acquired drug resistance approximately 1-2 years from the beginning of treatment. Multiple acquired resistance mechanisms including on-target EGFR mutations, phenotype transformation, and activation of bypass signaling molecules have been identified, but over 35% still remains unknown. CAGE, a cancer/testis antigen, was originally isolated from the sera of patients with gastric cancer and is known to regulate the autophagic flux in acquired resistance to EGFR TKI in NSCLC. Herein, the expression of CAGE was found in more than 50% of NSCLC patients using immunohistochemistry (IHC). Interestingly, the expression level was increased especially for the patients acquiring resistance to EGFR-TKIs. In addition, both PC-9/ER (Erlotinib-resistance cells) and H1975/OR (Osimertinib-resistant cells) cells demonstrated increased CAGE expression and autophagic flux, when compared with their parental cells. Thus, we developed the peptide drugs targeting the DEAD box domain of CAGE. This novel peptide effectively inhibited tumor cell proliferation in EGFR-TKI resistant cell line. Moreover, in Erlotinib-resistant patient-derived xenograft (PDX) mice, the peptide drug retarded tumor growth and enhanced anti-tumor efficacy. Collectively, our data suggest that CAGE plays a crucial role in the tumor progression and acquired resistance of EGFR TKI by the modulation of autophagic flux. Furthermore, we provided evidence that the inhibition of autophagy through CAGE- derived peptide could overcome the acquired resistance to EGFR TKIs in advanced/metastatic NSCLC patients. Citation Format: Jung-Young Shin, Min-Young Kim, Mi-Ran Lee, Hankyu Lee, Doyong Jeon, Seung Ryel Baek, Kim Joo Il, Jaemoon Koh, Dooil Jeoung, Jin Hyoung Kang. Inhibition of autophagy by CAGE targeting peptide retard tumor growth in non-small cell lung cancer of EGFR TKI resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1582.
Abstract 5252: Salsolinol suppresses the STAT3-EMT axis in liver carcinogenesis
Authors: Hyeon Jeong Oh, Seah Park, Hong-Kyung Yang, Hoon Ryu, Young-Joon Surh, Dae-Yong Kim, Hye-Kyung Na
Journal: Cancer Research (2023)

Abstract Liver cancer is one of the most common malignancies and a leading cause of death worldwide. However, it is still very difficult to treat and prevent liver cancer. Salsolinol (SAL) is an endogenous catechol isoquinoline generated by the condensation of dopamine with acetaldehyde, a major metabolite of ethanol. In the present study, we found that SAL inhibited the phosphorylation, dimerization, and subsequent nuclear translocation of STAT3 in a concentration-dependent manner in SK-Hep1 cells, a hepatic carcinoma cell line. SAL suppressed the expression of Cdk 4 and Cyclin D1, the major target protein of STAT3, and induced the cell cycle arrest at Go/G1 phase. However, SAL induced the expression of STAT1 in SK-Hep1 cells. In addition, SAL enhanced the expression of the cell cycle regulators such as p53 and p21 in SK-Hep1 cells. Epithelial-mesenchymal transition (EMT) promotes tumor invasion and metastasis in malignancies through STAT3 activation. SAL induced the expression of E-cadherin while suppressing the expression of Snail, N-cadherin, and Slug, which are related to EMT. SAL inhibited the migration of SK-Hep1 cells by suppressing the expression of MMP-9 and MMP-2. Furthermore, intraperitoneal injection of SAL reduced the number of tumors in the diethylnitrosamine (DEN)-induced liver carcinogenesis model without affecting the body weight change. Proliferative markers PCNA and KI-67 and p-STAT3 were down-regulated in the SAL-injected mice liver cancer tissue. The plasma level of alpha-fetoprotein, a tumor marker in the blood, was also reduced in the SAL-injected mice. Interestingly, SAL injection significantly reduced the anxiety-like behavior without affecting the locomotive activities in the DEN-induced hepatocellular carcinoma mouse model. Moreover, SAL injection recovered tyrosine hydroxylase, a key enzyme for producing dopamine from tyrosine in the substantia nigra compacta of DEN-treated mice. Together, SAL inhibits STAT3 signaling, thereby suppressing the cell cycle progression and EMT in SK-Hep1 cells, which may account for its anti-depressant and anti-carcinogenic activity in DEN-induced liver carcinogenesis. Citation Format: Hyeon Jeong Oh, Seah Park, Hong-Kyung Yang, Hoon Ryu, Young-Joon Surh, Dae-Yong Kim, Hye-Kyung Na. Salsolinol suppresses the STAT3-EMT axis in liver carcinogenesis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5252.
Abstract 4462: Immunoregulatory effects of NNMT-expressing cancer-associated fibroblasts
Authors: Janna Heide, Andras Piffko, Agnes J. Bilecz, Ethan A. Teich, Lisa Schweizer, Sayed R. Alhunayan, Kaiting Yang, Ernst Lengyel
Journal: Cancer Research (2023)

Abstract Nicotinamide N-methyltransferase (NNMT) is highly expressed in the stroma of several malignancies and has been shown to drive the transformation of resting fibroblasts into cancer-associated fibroblasts (CAFs) through epigenetic changes. Given that CAFs can promote immunosuppression in cancer, the aim of our study was to investigate the effect of NNMT-expressing CAFs on the tumor-immune environment. Using a co-culture system of normal fibroblasts and activated PBMCs, we found that IFN-γ produced by PBMCs upregulates NNMT expression in fibroblasts. We confirmed this mechanism in vivo in IFN-γ knockout mice and identified T cells as the main source of IFN-γ in the tumor. Gene expression and protein analysis showed that upregulation of NNMT in CAFs induces the secretion of the chemokine CXCL1, a critical chemoattractant for immunosuppressive myeloid-derived suppressor cells (MDSCs). Upregulation of NNMT induces CXCL1 secretion directly through promoter hypomethylation, and in vitro migration assays show that NNMT-expressing CAFs recruit high numbers of MDSCs. Using spectral flow cytometry, we analyzed the tumor-immune cell infiltration in whole-body NNMT-knockout mice and discovered that NNMT knockout of the stroma significantly reduced the abundance of MDSCs and increased the number of functional CD8+ T cells. Increased T cell cytotoxicity was associated with a significant reduction in tumor burden in the syngeneic ID8 ovarian and MC38 colon cancer models. These findings were confirmed after adoptive transfer of NNMT-wildtype immune cells into irradiated whole-body NNMT-knockout mice. Moreover, in scRNA-seq data of various human malignancies, we found a strong correlation between NNMT and CXCL1 expression in CAFs. In summary, our results support a model in which cancer cells induce IFN-γ secretion by T-cells, thereby upregulating NNMT expression in fibroblasts, leading to CXCL1 secretion. CXCL1 secreted by CAFs recruits MDSCs to the tumor, which in turn suppress the anti-tumor T cell response. Citation Format: Janna Heide, Andras Piffko, Agnes J. Bilecz, Ethan A. Teich, Lisa Schweizer, Sayed R. Alhunayan, Kaiting Yang, Ernst Lengyel. Immunoregulatory effects of NNMT-expressing cancer-associated fibroblasts. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4462.
Abstract 1315: NETs act as immunosuppressive agents within lymph nodes during cancer
Authors: Ariane Brassard, Xin Su, Iqraa Dhoparee-Doomah, Sabrina Leo, Lixuan Feng, France Bourdeau, Betty Giannias, Corissa Larson, Qian Qiu, Jonathan Spicer, Lorenzo Ferri, Jonathan Cools-Lartigue
Journal: Cancer Research (2023)

Abstract Metastasis is responsible for 90% of all cancer-related deaths, making it the most significant challenge in cancer treatment for clinicians worldwide. Metastasis is thought to occur in a stepwise process, in which local lymph nodes (LNs) are first colonized by tumour cells before proceeding to distal organs. However, the mechanism by which LN metastasis facilitates distal metastasis is poorly understood. LNs undergo environmental changes to accommodate tumour cell growth within, notably by shifting the environment towards immunosuppression to shut down anti-tumour immune cells. This immunosuppressive environment is critical for the establishment of LN metastases, as cytotoxic CD8 T cells will otherwise neutralize incoming circulating tumour cells. Neutrophils are among the first cells recruited to tumour-draining LNs to mediate the environmental shift, and yet their method of action has not been fully elucidated. They have recently been found to secrete NETs within LNs during cancer, which are pro-inflammatory web-like formations of DNA decorated with antimicrobial peptides. While NETs have been shown to exert pro-tumour effects in the tumour microenvironment and to facilitate metastasis as a whole, their role in LNs has never been explored. Using a NETs deficient mouse model (PAD4-/-), we report that NETs deposition within the tumour-draining LNs of mice upregulates the Treg population while simultaneously downregulating anti-tumour CD8 T cell proliferation and activation. Following these findings, we performed an in vitro suppression assay and found that NETs-educated Tregs hinder the expansion of CD8 T cells more than non-NETs-educated Tregs. Finally, through an induced metastasis mouse model, we have observed that tumour-draining LN resection as well as the absence of NETs protects against the development of distal metastasis, and decreases body-wide inflammation as seen by a lowered Neutrophil-to-Lymphocyte ratio in the circulation. Taken together, these findings highlight the role of NETs deposition in LNs as a key player in disease progression and bring forward a potential target for anti-metastatic drug development. Citation Format: Ariane Brassard, Xin Su, Iqraa Dhoparee-Doomah, Sabrina Leo, Lixuan Feng, France Bourdeau, Betty Giannias, Corissa Larson, Qian Qiu, Jonathan Spicer, Lorenzo Ferri, Jonathan Cools-Lartigue. NETs act as immunosuppressive agents within lymph nodes during cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1315.